A Multicenter Retrospective Study on the Clinical Features of Patients with Human Epidermal Growth Factor Receptor 2-Positive Colorectal Cancer (HGCSG2304)

A Multicenter Retrospective Study on the Clinical Features of Patients with Human Epidermal Growth Factor Receptor 2-Positive Colorectal Cancer (HGCSG2304) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A Multicenter Retrospective Study on the Clinical Features of Patients with Human Epidermal Growth Factor Receptor 2-Positive Colorectal Cancer (HGCSG2304) SHIHO KANEKO, KENTARO SAWADA, Kazuteru Hatanaka, Masayoshi Dazai, and 19 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9232486/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 5 You are reading this latest preprint version Abstract Background In metastatic colorectal cancer (mCRC), human epidermal growth factor receptor 2 (HER2)-positive disease is an important molecular subtype for targeted therapy; however, its prevalence is low and real-world data remain limited. Methods A multicenter retrospective study of patients with HER2-positive mCRC diagnosed between 2010 and 2023 at 14 institutions in Japan was conducted. In patients with RAS wild-type tumors, clinical outcomes were compared based on the molecular targeted agent (anti- epidermal growth factor receptor [EGFR] antibody or bevacizumab) combined with first-line chemotherapy. In patients treated with trastuzumab plus pertuzumab, clinical outcomes and safety including infusion-related reactions (IRRs) were assessed. Results Forty-five patients were included. In patients with RAS wild-type tumors, clinical outcomes were comparable between the anti-EGFR antibody ( n = 17) and bevacizumab ( n = 9) groups (progression-free survival: 15.6 vs . 12.0 months; hazard ratio: 0.94, 95% confidence interval: 0.38–2.35, overall survival: 38.4 vs . 32.0 months; hazard ratio: 0.91, 95% confidence interval: 0.30–2.74, p = 0.87). Twenty patients received trastuzumab plus pertuzumab, with a median progression-free survival of 3.1 months and an objective response rate of 10%. Greater benefit was observed in patients with RAS wild-type and HER2 immunohistochemistry 3+ tumors (objective response rate 28.6%). IRRs occurred in 14.2% of patients who received prophylactic antihistamines and 41.7% of those who did not. Conclusions In patients with HER2-positive mCRC, first-line treatment efficacy appeared comparable between the anti-EGFR antibody and bevacizumab groups. Trastuzumab plus pertuzumab demonstrated clinical activity, emphasizing the importance of appropriate patient selection and management of IRRs. human epidermal growth factor receptor 2-positive metastatic colorectal cancer trastuzumab plus pertuzumab RAS wild-type first-line chemotherapy infusion-related reactions Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Metastatic colorectal cancer (mCRC) remains one of the leading causes of cancer-related morbidity and mortality worldwide [1]. In mCRC, recent advances in the development of molecular target agents have enabled treatment stratification based on specific molecular subtypes, including distinct genetic alterations. Among these, human epidermal growth factor receptor 2 (HER2)-positive mCRC is a particularly clinically significant subtype due to the efficacy of HER2-targeted therapies, such as the combination of trastuzumab plus pertuzumab (Tmab+Per) in the MyPathway and the TRIUMPH studies [2, 3], and trastuzumab deruxtecan in the DESTINY-CRC 01 and DESTINY-CRC02 trials [4, 5]. However, HER2-positive disease occurs in only approximately 3–5% of all mCRC cases [6, 7], so real-world data of clinical characteristics, optimal treatment strategies, and outcomes of HER2-targeted therapy remain limited, leaving several clinically important questions unresolved. First, it is unclear whether an anti-epidermal growth factor receptor (EGFR) antibody or bevacizumab is the optimal molecular targeted agent as first-line treatment for RAS wild-type HER2-positive mCRC patients, who reportedly constitute the majority of HER2-positive colorectal cancer cases. Currently, both molecular targeted agents are available for first-line treatment of RAS wild -type mCRC. However, multiple studies have reported that anti-EGFR antibody therapy is less effective in later-line treatment of HER2-positive mCRC [6, 8, 9]. Indeed baseline circulating tumor DNA analysis [10] in the PARADIGM trial demonstrated higher efficacy of anti-EGFR agents in population without multiple genetic alterations, including HER2 amplification. Consequently, there is no established consensus on the optimal molecular targeted agent for first-line treatment in patients with RAS wild-type HER2-positive mCRC. Second, there is a lack of real-world data on the efficacy and safety of Tmab+Per combination therapy, which is currently the most widely used HER2-targeted regimen in clinical practice. The objective response rate (ORR) of this combination in clinical trials is approximately 20–30% [2, 3], but the data from real-world practice remain limited, making it important to investigate which patients are most likely to benefit. Furthermore, infusion-related reactions (IRRs) have been reported particularly during early treatment cycles [3, 11], but information on the strategies for safe administration in routine clinical practice remains insufficient. Therefore, we conducted a multicenter retrospective observational study to address these clinical questions in patients with HER2-positive mCRC. Patients and Methods Patients, Study Design, and Definition of Human Epidermal Growth Factor Receptor 2-Positivity This multicenter retrospective observational study included patients diagnosed with HER2-positive mCRC at 14 institutions in Japan between December 2010 and December 2023. HER2-positive tumors were defined by at least one of the following criteria: i) an immunohistochemistry (IHC) score of 3+, ii) a HER2/CEP17 ratio of 2.0 or greater by fluorescence in situ hybridization (FISH), and iii) HER2 gene amplification detected by next-generation sequencing (NGS) using tissue or liquid biopsy, defined as a copy number of 2.18 or more. RAS/BRAF Mutation and Microsatellite Instability/Mismatch Repair Status RAS and BRAF V600E mutations were analyzed using the RASKET-B kit (Medical & Biological Laboratories, Tokyo, Japan). Microsatellite instability (MSI) status was determined either by a polymerase chain reaction-based MSI panel or by IHC staining for mismatch repair proteins (MutL homolog 1, MutS homolog 2, MutS homolog 6, and Postmeiotic segregation increased 2). Treatment Outcomes In patients with RAS wild-type tumors, the efficacy of first-line doublet or triplet chemotherapy combined with either anti-EGFR antibody or bevacizumab was evaluated. Progression-free survival (PFS) was defined as the time from initiation of first-line therapy to disease progression or death from any cause. Overall survival (OS) was defined as the time from initiation of first-line therapy to death from any cause. ORR was assessed according to the Response Evaluation Criteria in solid tumor version 1.1. The efficacy and safety of Tmab+Per were analyzed in patients who initiated this regimen by July 2024. ORR, disease control rate (DCR), and PFS were assessed according to the Response Evaluation Criteria in solid tumor version 1.1. Adverse events (AEs) were evaluated using the Common Terminology Criteria for Adverse Events version 5.0. The data cutoff date was December 31, 2025. Statistical Analysis Statistical analyses were performed using EZR version 1.68 (Saitama Medical Center, Jichi Medical University, Saitama, Japan) and IBM SPSS Statistics version 29.0.1.0 (IBM Japan Ltd., Tokyo, Japan). Categorical variables were evaluated using Fisher's exact test. Survival curves were estimated using the Kaplan–Meier method, and hazard ratios (HRs) were calculated using the Cox proportional hazards model. Comparison of PFS between treatment groups was performed using the log-rank test. Statistical significance was defined as a p -value less than 0.05. Ethical Considerations This study was conducted in accordance with the Declaration of Helsinki and approved by the institutional review boards of all participating institutions. Due to the retrospective nature of the study, the requirement for written informed consent was waived. Results B aseline Characteristics of Study Participants A total of 45 patients with HER2-positive mCRC were included in this study. Patient clinical characteristics for all 45 patients are shown in Table 1. The median age was 63 years (range, 36–81 years), and 64.4% were male. HER2 status was determined as follows: 26 patients had HER2 IHC3+, 15 patients were FISH positive (excluding IHC3+), and 4 patients had HER2 gene amplification detected by NGS (excluding IHC3+ and FISH positive). Primary tumors were located on the left side of the colon or rectum in 73.3% of patients and on the right side in 26.7%. Metastatic sites were most commonly the liver (66.7%), followed by the lung (35.6%). Regarding molecular profiles, 73.3% of patients were RAS wild-type, and all patients were negative for the BRAF V600E mutation and MSI-high (MSI-H) status. Detailed results of HER2 testing by IHC, FISH, and NGS, along with corresponding RAS status for each patient, are summarized in Supplementary Table 1. Of 33 patients with RAS wild-type tumors, nine received anti-EGFR and seventeen received bevacizumab combined with chemotherapy as first-line treatment (anti-EGFR antibody vs . bevacizumab cohort). Twenty of the 45 patients received Tmab+Per therapy (Tmab+Per cohort). The study flowchart is shown in Figure 1. Efficacy of First-Line Therapy in RAS Wild-Type Patients Patient characteristics for those with HER2-positive and RAS wild-type tumors who received first-line chemotherapy with an anti-EGFR antibody ( n = 17) or bevacizumab ( n = 9) are shown in Supplementary Table 2. PFS and OS according to first-line regimens in patients with HER2 positive/ RAS wild-type are shown in Figures 2A and 2B. At a median follow-up of 43.3 months, first-line PFS was similar between the anti-EGFR antibody ( n = 17) and bevacizumab ( n = 9) groups (median: 15.6 vs . 12.0 months, HR = 0.94, 95% confidence interval: 0.38–2.35, p = 0.89). OS was also similar between the two groups (median: 38.4 vs . 32.0 months; HR = 0.91, 95% confidence interval: 0.30–2.74, p = 0.87). The ORR was 58.8% in the anti-EGFR antibody group and 100% in the bevacizumab group, with details provided in Supplementary Table 3. Efficacy and Safety Profile of Trastuzumab plus Pertuzumab Therapy A total of twenty patients received Tmab+Per therapy. Baseline characteristics of these patients are summarized in Table 2. The median age was 65 years (range, 36–80), with 9 females (45.0%) and 11 males (55.0%). Primary tumors were located more frequently on the left side of the colon or rectum (75.0%) than on the right side (25.0%). Regarding HER2 status, 9 patients (45.0%) had IHC 3+, 7 patients (35.0%) were FISH positive (excluding IHC 3+), and 4 patients (20.0%) had HER2 gene amplification confirmed by NGS (excluding IHC 3+ and FISH positive). RAS wild-type status was identified in 15 patients (75.0%), while 5 patients (25.0%) carried RAS mutations. Tmab+Per therapy was administered mainly in later treatment lines; 4 patients (20.0%) as second-line, 1 patient (5.0%) as third-line, 7 patients (35.0%) as fourth-line, 5 patients (25.0%) as fifth-line, and 3 patients (15.0%) as sixth-line therapy. Median relative dose intensity was 97.9% for trastuzumab and 97.7% for pertuzumab, indicating good treatment compliance. Figure 3 shows the PFS for Tmab+Per therapy, along with each patient’s HER2-IHC score, RAS status, prior anti-EGFR therapy, and line of therapy. Median PFS for all patients was 3.1 months. The ORR and DCR were 10.0% and 55.0%, respectively. Efficacy by RAS status and HER2 IHC score is shown in Figure 4. Patients most likely to benefit from Tmab+Per treatment were those with RAS wild-type and IHC3+ tumors (median PFS 4.1 months, ORR 28.6%, DCR 71.4%), followed by RAS wild-type without IHC3+ (median PFS 2.2 months, ORR 0%, DCR 37.5%). Among five patients with RAS mutations, only one achieved disease control, with the poorest treatment response (median PFS 2.2 months). AEs related to Tmab+Per therapy were generally manageable (Table 3). The most frequently observed AEs (any grade) included fatigue (40.0%), anorexia (30.0%), anemia (30.0%), and IRRs (30.0%). Grade 3 or more AEs occurred in 15% of patients and included diarrhea (5.0%), IRRs (5.0%), perimandibular inflammation (5.0%), cellulitis (5.0%), and ureteral stones (5.0%). One patient discontinued Tmab+Per therapy due to Grade 4 IRRs. The frequency of IRRs according to premedication is shown in Table 4. Among 19 patients with available premedication data, IRRs occurred in six patients (three Grade 1, two Grade 2, and one Grade 4). The incidence of IRRs was similar in patients who received acetaminophen or nonsteroidal anti-inflammatory drugs as premedication (n = 9) compared with those who did not (n = 11) (33.0% vs. 30.0%, p = 1.00). IRRs were numerically lower in patients who received antihistamines (n = 7) compared with those who did not (n = 12), although the difference was not statistically significant (14.2% vs. 41.7%, p = 0.35). Discussion In this multicenter retrospective study, we investigated the real-world clinical characteristics and treatment outcomes of patients with HER2-positive mCRC. To our knowledge, this study represents the largest multicenter real-world clinical cohort to date. Our data provide unique insights into the clinical characteristics, treatment outcomes, and premedication strategies of IRRs in this rare molecular subtype in routine practice. The majority of patients in our cohort had left-sided primary tumors with RAS wild-type status and liver metastases, consistent with previous reports [6, 12]. Prior studies have shown that HER2 amplification is largely mutually exclusive with MSI-H [12], and no patients in this study harbored MSI-H tumors or BRAF V600E mutations. Furthermore, compared with prior clinical evidence [3], our real-world cohort included a relatively higher proportion of patients defined as HER2-positive by FISH or NGS despite the absence of HER2IHC3+ overexpression. In prospective clinical trials such as DESTINY-CRC01 and TRIUMPH, approximately 75% of patients were classified as having HER2 IHC3+ tumors [3] [4], whereas only 57.8% (26/45) of patients exhibited HER2 IHC3+ overexpression in our study. Because IHC results are not mandatory for the use of anti-HER2 therapy in clinical practice, unlike clinical trials, the presence of a few patients ( n = 4, 8.9%) with missing IHC results contributed to this difference. However, the primary reason was the high number of cases showing HER2 gene amplification despite IHC2+ ( n = 13, 28.9%). HER2 IHC in our study was performed using the same antibody clone (VENTANA 4B5) as in prospective trials; however, scoring was conducted locally at each participating institution rather than via centralized review. This difference in assessment methodology may have introduced inter-observer variability and partly explains the discrepancy in HER2 expression profiles between our real-world cohort and clinical trial populations. These findings suggest that when tumors are classified as HER2 IHC2+ by local assessment, confirmatory testing with FISH or NGS may help identify additional tumors with HER2 gene amplification. In first-line chemotherapy for patients with RAS wild-type tumors, there were no statistically significant differences in efficacy between the bevacizumab-containing and anti-EGFR antibody groups. Although HER2 overexpression has been proposed as a mechanism of resistance to anti-EGFR therapy based on preclinical and retrospective late-line treatment data [13], a recent pooled exploratory analysis of eight randomized trials demonstrated that HER2 positivity did not predict differential benefit from first-line chemotherapy combined with either anti-EGFR antibodies or bevacizumab [14]. In that analysis, no significant interaction between HER2 status and the choice of biologic agent was observed for PFS, OS, or ORR, indicating that HER2 positivity alone should not guide selection between anti-EGFR- or bevacizumab-based regimens in the first-line setting. Therefore, the lack of significant differences observed in our study aligns with these findings. Clinically, these results support an individualized treatment approach in which the selection of biologic agents is guided primarily by patient-specific factors rather than expected differences in efficacy. In particular, the distinct toxicity profiles of anti-EGFR antibodies (e.g., skin toxicity) and bevacizumab (e.g., hypertension and proteinuria) should be carefully considered when choosing the most appropriate targeted agent for each patient. In the present study, among patients treated with Tmab+Per, the ORR was 10.0%, DCR was 55.0%, and median PFS was 3.1 months. Compared with previously reported prospective studies, such as the MyPathway and TRIUMPH trials [2] [3], median PFS was generally comparable, whereas the ORR was lower in our cohort. Several differences in patient characteristics may explain this discrepancy. Compared with prior clinical trials, patients treated with Tmab+Per in our study were older, had a higher proportion of RAS -mutant tumors, and showed a lower frequency of HER2 IHC3+ expression. Among these factors, RAS mutation status and HER2 IHC score were particularly important. As anti-HER2 therapy is known to be less effective in RAS -mutant tumors, in the MyPathway study, Tmab+Per demonstrated substantially lower activity in patients with RAS -mutant tumors (ORR 8%) compared with patients with RAS wild-type disease (ORR 40%) [2]. The importance of HER2 expression level for anti-HER2 therapy has been demonstrated in the DESTINY-CRC01 trial evaluating trastuzumab deruxtecan, in which patients with HER2 IHC3+ tumors achieved higher ORR (57.5%) and longer median PFS (8.3 months), whereas limited benefit was observed in patients with HER2 IHC2+/FISH positive tumors (ORR 7.7%; median PFS 4.1 months) [4]. Consistently, in our study, treatment efficacy was highest in patients with RAS wild-type and IHC3+ tumors. Taken together, these findings indicate that careful patient selection based on molecular characteristics, including RAS mutation status and HER2 expression level, is crucial to maximize the benefit of late-line treatment, including anti-HER2 therapy, in metastatic colorectal cancer. AEs associated with Tmab+Per were generally manageable, suggesting that this combination therapy can be administered with an acceptable safety profile in real-world clinical practice. In the TRIUMPH trial, IRRs, a characteristic AE of Tmab+Per therapy, were reported in 47.0% of patients [3]. IRRs are clinically relevant because their occurrence may lead to treatment interruption or delay, potentially compromising treatment continuity. Therefore, appropriate management and prevention of IRRs are important in clinical practice. In our real-world cohort, IRRs were observed in 31.6% of patients, demonstrating an incidence comparable to that reported in clinical trials. Notably, patients who received antihistamine premedication experienced a numerically lower incidence of IRRs compared with those who did not receive antihistamines (14.2% vs . 41.7%). In clinical practice, premedication with antihistamines or nonsteroidal anti-inflammatory drugs is commonly used to prevent IRRs associated with chimeric monoclonal antibodies such as rituximab [15, 16]. In breast cancer, corticosteroid premedication has also been suggested to reduce the risk of IRRs during trastuzumab therapy in retrospective studies [17]. However, there are currently no prospective or retrospective studies that have specifically evaluated the efficacy of premedication, including corticosteroids or antihistamines, for the prevention of IRRs associated with trastuzumab or pertuzumab therapy in patients with metastatic colorectal cancer. Our findings suggest that antihistamine premedication may reduce the risk of IRRs in this setting. Despite the clinical relevance of these real-world findings, several limitations should be acknowledged. First, this study was limited by its retrospective observational design, which may have resulted in incomplete clinical data and variability in the timing of response assessment and AE reporting. Second, the relatively small sample size, reflecting the rarity of HER2-positive mCRC, may have limited the statistical power to detect differences between treatment groups. Third, there was substantial heterogeneity in patient characteristics and treatment strategies. In particular, the line of therapy at which Tmab+Per was administered varied widely, from third-line to later-line settings, which may have influenced both efficacy and safety outcomes. Fourth, methods used to determine HER2 status were not uniform across institutions and included IHC, FISH, and NGS. This heterogeneity may have introduced variability in the identification of HER2-positive tumors and potentially influenced the study results. Fifth, OS may have been affected by subsequent therapies administered after disease progression. Because post-progression treatment were not standardized in this retrospective study, the impact of individual treatment strategies, including first-line biologic selection and anti-HER2 therapy, on OS should be interpreted with caution. Conclusions In clinical practice, first-line treatment regimens should be selected based on patient characteristics, including tumor biomarkers and the distinct toxicity profiles of available therapies. The Tmab+Per combination therapy was effective in real-world clinical settings; however, appropriate patient selection and careful management of IRRs are critical to optimize treatment outcomes. Declarations Acknowledgments The authors would like to thank all participating patients and their families. Authors’ Contributions Shiho Kaneko and Kentaro Sawada conceived and designed the study. Shiho Kaneko developed the study protocol and obtained ethical approval. Shiho Kaneko collected and curated the data. Kentaro Sawada contributed to data collection and data curation. Kazuteru Hatanaka, Hiroshi Nakatsumi, Masayoshi Dazai, Takayuki Ando, Masahito Kotaka, Yasushi Tsuji, Michio Nakamura, Osamu Muto, Takashi Meguro, Takahiro Ishii, Atsushi Sato, and Susumu Sogabe collected data at their respective institutions. Shiho Kaneko and Kentaro Sawada performed the statistical analysis. Shiho Kaneko and Kentaro Sawada drafted the manuscript. Shintaro Sawaguchi, Tatsuya Yokoyama, Koichi Ishida, Kazuaki Harada, Yasuyuki Kawamoto, Satoshi Yuki, Naoya Sakamoto, Yu Sakata, and Yoshito Komatsu critically revised the manuscript. Yoshito Komatsu supervised the study as the principal investigator and provided overall project oversight. All authors reviewed and approved the final manuscript. Funding This research received no external funding. Data Availability The datasets generated and/or analyzed during the current multicenter retrospective study are available from the corresponding author on reasonable request, subject to approval by the participating institutions. Declarations: Competing interests Masahito Kotaka, Yasushi Tsuji, Satoshi Yuki, and Yoshito Komatsu have received honoraria from Chugai Pharmaceutical Co., Ltd. The remaining authors declare that they have no conflicts of interest. Consent to participate The requirement for obtaining informed consent from participants was waived owing to the retrospective nature of this study. Ethical approval The study was conducted in accordance with the principles outlined in the Declaration of Helsinki and was approved by the Ethics Committee of Hokkaido University Hospital (Clinical Research Number: IRB 023-0470). 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Patient characteristics N=45 (%) Age, year Median (range) 63 (36-81) Sex Female 16 (35.6) Male 29 (64.4) ECOG PS 0 30 (66.7) ≥1 15 (33.3) Primary tumor location Left 33 (73.3) Right 12 (26.7) Metastatic site Liver 30 (66.7) Lung 16 (35.6) Lymph nodes 11 (24.4) Peritoneal dissemination 10 (22.2) HER2 positivity diagnosed methods IHC 3+ 26 (57.8) FISH positive (except IHC3+) 15 (28.9) HER2 amp on NGS (except IHC 3+ or FISH positive) 4 (13.3) RAS status Wild 33 (73.3) Mutant 12 (26.7) BRAF V600E status Wild 45 (100) Mutant 0 (0) MSI status Non MSI-H 45 (100) MSI-H 0 (0) Abbreviation: ECOG PS, Eastern Cooperative Oncology Group performance status; MSI-H, microsatellite instability-high; IHC, immunohistochemistry; FISH, fluorescence in situ hybridization; NGS, next-generation sequencing. Table 2. Baseline characteristics of patients who received trastuzumab plus pertuzumab therapy N=20 (%) Age, year Median (range) 65 (36-80) Sex Female 9 (45.0) Male 11 (55.0) Primary tumor location Left 15 (75.0) Right 5 (25.0) HER2 status IHC 3+ 9 (45.0) IHC 2+ and FISH + 7 (35.0) HER2 amplification on NGS or FISH 4 (20.0) RAS status Wild 15 (75.0) Mutant 5 (25.0) Treatment lines 2nd 4 (20.0) 3rd 1 (5.0) 4th 7 (35.0) 5th 5 (25.0) 6th 3 (15.0) RDI of Trastuzumab (%) Median (range) 97.9 (68.6-100) RDI of Pertuzumab (%) Median (range) 97.7 (61.5-100) Previous treatment Anti-EGFR antibody 13 (65.0) Fluoropyrimidine 19 (95.0) Oxaliplatin 19 (95.0) Irinotecan 17 (85.0) Bevacizumab/Ramucirumab/Aflibercept 18 (90.0) Regorafenib 7 (35.0) Trifluridine/tipiracil 10 (50.0) Premedication Antihistamine ± NSAIDs 5 (25.0) No antihistamine ± NSAIDs 12 (60.0) Abbreviations: FISH, fluorescence in situ hybridization; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; NGS, next-generation sequencing; NSAIDs, non-steroidal anti-inflammatory drugs; RDI, relative dose intensity. Table 3. AEs related Tmab+Per treatment CTCAE v5.0, grade, N=20 1 2 3 4 Any grade ≥Grade 3 White blood cell decreased 1 1 0 0 2 (10.0) 0 (0) Neutrophil count decreased 0 1 0 0 1 (5.0) 0 (0) Anemia 3 2 1 0 6 (30.0) 1 (5.0) Platelet count decreased 2 1 0 0 3 (15.0) 0 (0) Nausea 2 0 0 0 2 (10.0) 0 (0) Anorexia 3 3 0 0 6 (30.0) 0 (0) Fatigue 5 3 0 0 8 (40.0) 0 (0) Diarrhea 3 0 1 0 4 (20.0) 1 (5.0) Fever 3 0 0 0 3 (15.0) 0 (0) Infusion related reactions 3 2 0 1 6 (30.0) 1 (5.0) Perimandibular inflammation 0 0 1 0 1 (5.0) 1 (5.0) Cellulitis 0 0 1 0 1 (5.0) 1 (5.0) Ureteral stones 0 0 1 0 1 (5.0) 1 (5.0) Abbreviation: AEs, adverse events; CTCAE, Common Terminology Criteria for Adverse Events; Tmab, trastuzumab; Per, pertuzumab. Table 4. Frequency of Infusion Related Reactions (IRRs) according to the premedication Infusion Related Reactions NSAIDs or Acetaminophen (+) NSAIDs or Acetaminophen (-) Total Antihistamine (+) 1/6 (16.6%) 0/1 (0.0%) 1/7 (14.2%) Antihistamine (-) 2/3 (66.7%) 3/9 (33.3%) 5/12 (41.7%) Total 3/9 (33.3%) 3/10 (30.0%) 6/19 (31.6%) Abbreviation: NSAIDs, nonsteroidal anti-inflammatory drugs. Supplementary Files HGCSG2304suppletablever1.3.docx Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Major revisions 07 May, 2026 Reviewers agreed at journal 20 Apr, 2026 Reviewers invited by journal 20 Apr, 2026 Editor assigned by journal 26 Mar, 2026 First submitted to journal 26 Mar, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9232486","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":626362460,"identity":"7e4648bb-e19f-4254-9a46-ae91d940da89","order_by":0,"name":"SHIHO KANEKO","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8UlEQVRIiWNgGAWjYDACCcbGBwwHgAweBsYHIIqPsBbmZgOoFmYDEMVGWAt7mwRUC5sESICgFvnZjUBbztjl8fMcPlb5NcdOho2B+eGjG3i0GNw5CPTLjeRiyd62tNuy25KBDmMzNs7Bp0UiEWjLB+bEDed5zG5LbmMGauFhk8anRX5GItAvH+oT9wO1FEtuqyesheEGSMuNw4kbeHvMGD9uO0xYi8ENoMMSzhxPnHHmWLI047bjPGzMBPwiPyP94YMPx6oT+3uSD378ua3anp+9+eFjvA4DgQQozcwDJgkpRwaMP0hRPQpGwSgYBSMGAAB9cEnNe96VBwAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-8862-7697","institution":"Hokkaido University Hospital: Hokkaido Daigaku Byoin","correspondingAuthor":true,"prefix":"","firstName":"SHIHO","middleName":"","lastName":"KANEKO","suffix":""},{"id":626362461,"identity":"994c78a4-d57d-4cbf-9f80-291d2c2fd605","order_by":1,"name":"KENTARO SAWADA","email":"","orcid":"https://orcid.org/0000-0001-7952-2765","institution":"Kushiro Rosai Hospital: Kushiro Rosai 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Center","correspondingAuthor":false,"prefix":"","firstName":"Hiroshi","middleName":"","lastName":"Nakatsumi","suffix":""},{"id":626362465,"identity":"39dc294d-7e4b-4f6f-a124-3671de30b094","order_by":5,"name":"Takayuki Ando","email":"","orcid":"","institution":"University of Toyama: Toyama Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Takayuki","middleName":"","lastName":"Ando","suffix":""},{"id":626362466,"identity":"3fe53ea9-898d-4b20-82ce-21e98641c483","order_by":6,"name":"Masahito Kotaka","email":"","orcid":"","institution":"Sano Hospital","correspondingAuthor":false,"prefix":"","firstName":"Masahito","middleName":"","lastName":"Kotaka","suffix":""},{"id":626362467,"identity":"e3026ac9-7e50-498a-b101-978e1bdfcfb8","order_by":7,"name":"Yasushi Tsuji","email":"","orcid":"","institution":"Tonan 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Center","correspondingAuthor":false,"prefix":"","firstName":"Susumu","middleName":"","lastName":"Sogabe","suffix":""},{"id":626362474,"identity":"7acd2149-bf8b-49f7-9300-53d5670fc44c","order_by":14,"name":"Shintaro Sawaguchi","email":"","orcid":"","institution":"Hokkaido University Hospital: Hokkaido Daigaku Byoin","correspondingAuthor":false,"prefix":"","firstName":"Shintaro","middleName":"","lastName":"Sawaguchi","suffix":""},{"id":626362475,"identity":"1efefee9-d479-4acb-b7c4-ad5f8c692670","order_by":15,"name":"Tatsuya Yokoyama","email":"","orcid":"","institution":"Hokkaido University Hospital: Hokkaido Daigaku Byoin","correspondingAuthor":false,"prefix":"","firstName":"Tatsuya","middleName":"","lastName":"Yokoyama","suffix":""},{"id":626362476,"identity":"bdb9b626-2fb1-47e0-b7c2-8a0b7b6e4625","order_by":16,"name":"Koichi Ishida","email":"","orcid":"","institution":"Hokkaido University Hospital: Hokkaido Daigaku Byoin","correspondingAuthor":false,"prefix":"","firstName":"Koichi","middleName":"","lastName":"Ishida","suffix":""},{"id":626362477,"identity":"50f5e919-5621-4917-ba5c-b2cd6e3accda","order_by":17,"name":"Kazuaki Harada","email":"","orcid":"","institution":"Hokkaido University Hospital: Hokkaido Daigaku Byoin","correspondingAuthor":false,"prefix":"","firstName":"Kazuaki","middleName":"","lastName":"Harada","suffix":""},{"id":626362478,"identity":"ef31f767-3240-4b65-b32a-13ceb0cceba9","order_by":18,"name":"Yasuyuki Kawamoto","email":"","orcid":"","institution":"National Cancer Center Hospital: Kokuritsu Gan Kenkyu Center Chuo Byoin","correspondingAuthor":false,"prefix":"","firstName":"Yasuyuki","middleName":"","lastName":"Kawamoto","suffix":""},{"id":626362479,"identity":"ca8c628e-9dc1-4544-ba54-bb0559872565","order_by":19,"name":"Satoshi Yuki","email":"","orcid":"","institution":"Hokkaido University Hospital: Hokkaido Daigaku Byoin","correspondingAuthor":false,"prefix":"","firstName":"Satoshi","middleName":"","lastName":"Yuki","suffix":""},{"id":626362480,"identity":"3615ebc7-01c4-46df-b0d6-b73e3372266f","order_by":20,"name":"Naoya Sakamoto","email":"","orcid":"","institution":"Hokkaido University Hospital: Hokkaido Daigaku Byoin","correspondingAuthor":false,"prefix":"","firstName":"Naoya","middleName":"","lastName":"Sakamoto","suffix":""},{"id":626362481,"identity":"d5149a68-4c85-4a11-822b-67006429a634","order_by":21,"name":"Yu Sakata","email":"","orcid":"","institution":"Misawa City Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yu","middleName":"","lastName":"Sakata","suffix":""},{"id":626362482,"identity":"a450f5f5-ed62-46e7-9109-0491ffbafdcf","order_by":22,"name":"Yoshito Komatsu","email":"","orcid":"","institution":"Hokkaido University Hospital: Hokkaido Daigaku Byoin","correspondingAuthor":false,"prefix":"","firstName":"Yoshito","middleName":"","lastName":"Komatsu","suffix":""}],"badges":[],"createdAt":"2026-03-26 09:56:38","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9232486/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9232486/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108181869,"identity":"d5321367-d6c8-4012-b204-3c3f84adf3ec","added_by":"auto","created_at":"2026-04-30 08:58:58","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":244434,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStudy flow\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 45 patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic colorectal cancer (mCRC) were identified. Among them, 12 patients had \u003cem\u003eRAS\u003c/em\u003e-mutant tumors, and 33 had \u003cem\u003eRAS\u003c/em\u003e wild-type (wt) tumors and were included in the analysis. Of the 33 \u003cem\u003eRAS\u003c/em\u003e wt patients, seven who received fluoropyrimidine monotherapy (with or without molecular targeted agents) or chemotherapy without molecular targets as first-line therapy were excluded from the comparative analysis. The remaining patients were classified into the anti-epidermal growth factor receptor (EGFR) antibody plus chemotherapy group (\u003cem\u003en\u003c/em\u003e = 17) and the bevacizumab plus chemotherapy group (\u003cem\u003en\u003c/em\u003e = 9) in the anti-EGFR antibody \u003cem\u003evs\u003c/em\u003e. bevacizumab (BV) cohort. In addition, 20 of the 45 patients received trastuzumab plus pertuzumab (Tmab+Per) and were included in the Tmab+Per cohort.\u003c/p\u003e\n\u003cp\u003emCRC, metastatic colorectal cancer; wt, wild-type; Tmab+Per, trastuzumab plus pertuzumab; EGFR, epidermal growth factor receptor; BV, bevacizumab\u003c/p\u003e","description":"","filename":"HGCSG2304Fig.1ver2.0.png","url":"https://assets-eu.researchsquare.com/files/rs-9232486/v1/56b533a73b20008c63189d2e.png"},{"id":108181401,"identity":"25e232a3-82e5-4767-a4bb-c3c67a27d595","added_by":"auto","created_at":"2026-04-30 08:58:36","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":232000,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eProgression-free survival\u003c/strong\u003e (\u003cstrong\u003ePFS) (A) and overall survival (OS) (B) according to first-line regimens in \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eRAS\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e wild-type (wt) patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Kaplan–Meier curves for PFS in \u003cem\u003eRAS\u003c/em\u003e wt patients treated with anti-EGFR antibody plus chemotherapy or BV plus chemotherapy as first-line treatment.\u003c/p\u003e\n\u003cp\u003e(B) Kaplan–Meier curves for OS in \u003cem\u003eRAS\u003c/em\u003e wt patients according to first-line therapy.\u003c/p\u003e\n\u003cp\u003ePFS, progression-free survival; OS, overall survival; wt, wild-type; EGFR, epidermal growth factor receptor; BV, bevacizumab\u003c/p\u003e","description":"","filename":"HGCSG2304Fig.2ver2.0.png","url":"https://assets-eu.researchsquare.com/files/rs-9232486/v1/2ad17177dbe5f84e5bd3e45d.png"},{"id":108181362,"identity":"b7501ec4-ef51-493e-b87d-2e02b98ccb1d","added_by":"auto","created_at":"2026-04-30 08:58:34","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":167092,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eProgression-free survival (PFS) of trastuzumab plus pertuzumab (Tmab+Per) treatment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSwimmer plot showing PFS in individual patients who received Tmab+Per. Each horizontal bar represents the duration of PFS (months) for each patient. Colors indicate the best tumor response: partial response (PR), stable disease (SD), and progressive disease (PD). Baseline characteristics, including HER2 immunohistochemistry (IHC) status, \u003cem\u003eRAS\u003c/em\u003e status, prior anti-EGFR therapy, and line of therapy, are shown on the left. An asterisk (*) indicates a censored case due to treatment discontinuation caused by an adverse event. The remaining patients experienced progression events.\u003c/p\u003e\n\u003cp\u003ePFS, progression-free survival; PR, partial response; SD, stable disease; PD, progressive disease; IHC, immunohistochemistry; EGFR, epidermal growth factor receptor\u003c/p\u003e","description":"","filename":"HGCSG2304Fig.3ver2.0.png","url":"https://assets-eu.researchsquare.com/files/rs-9232486/v1/21fa901e3f88153d8cebfa42.png"},{"id":108072710,"identity":"1fc24e0f-1d08-4937-81eb-98a68fdfd817","added_by":"auto","created_at":"2026-04-29 06:15:06","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":230201,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEfficacy of trastuzumab plus pertuzumab therapy based on \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eRAS\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e status and human epidermal growth factor receptor 2 (HER2)\u003c/strong\u003e \u003cstrong\u003eimmunohistochemistry (IHC) score\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eObjective response rate (ORR) and disease control rate (DCR) are shown according to \u003cem\u003eRAS\u003c/em\u003e mutation status and HER2 IHC score. ORR is indicated by blue bars, and DCR by orange bars.\u003c/p\u003e\n\u003cp\u003eORR, objective response rate; DCR, disease control rate; IHC, immunohistochemistry\u003c/p\u003e","description":"","filename":"HGCSG2304Fig.4ver2.0.png","url":"https://assets-eu.researchsquare.com/files/rs-9232486/v1/4e45584c993eb280442f807a.png"},{"id":108183778,"identity":"077f7146-7117-4701-8783-8e4967c256f6","added_by":"auto","created_at":"2026-04-30 09:02:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1118491,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9232486/v1/f2da8f36-5675-4f11-8a18-2a9562c6f877.pdf"},{"id":108072707,"identity":"f8bb828e-aa7e-4448-8ae4-28dcd2ad8bac","added_by":"auto","created_at":"2026-04-29 06:15:06","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":30816,"visible":true,"origin":"","legend":"","description":"","filename":"HGCSG2304suppletablever1.3.docx","url":"https://assets-eu.researchsquare.com/files/rs-9232486/v1/02b8b06d11c43316144fd342.docx"}],"financialInterests":"","formattedTitle":"A Multicenter Retrospective Study on the Clinical Features of Patients with Human Epidermal Growth Factor Receptor 2-Positive Colorectal Cancer (HGCSG2304)","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMetastatic colorectal cancer (mCRC) remains one of the leading causes of cancer-related morbidity and mortality worldwide [1]. In mCRC, recent advances in the development of molecular target agents have enabled treatment stratification based on specific molecular subtypes, including distinct genetic alterations. Among these, human epidermal growth factor receptor 2 (HER2)-positive mCRC is a particularly clinically significant subtype due to the efficacy of HER2-targeted therapies, such as the combination of trastuzumab plus pertuzumab (Tmab+Per) in the MyPathway and the TRIUMPH studies [2, 3], \u0026nbsp;and trastuzumab deruxtecan \u0026nbsp;in the DESTINY-CRC 01 and DESTINY-CRC02 trials [4, 5]. However, HER2-positive disease occurs in only approximately 3\u0026ndash;5% of all mCRC cases [6, 7], so real-world data of clinical characteristics, optimal treatment strategies, and outcomes of HER2-targeted therapy remain limited, leaving several clinically important questions unresolved.\u003c/p\u003e\n\u003cp\u003eFirst, it is unclear whether an anti-epidermal growth factor receptor (EGFR) antibody or bevacizumab is the optimal molecular targeted agent as first-line treatment for \u003cem\u003eRAS\u003c/em\u003e wild-type HER2-positive mCRC patients, who reportedly constitute the majority of HER2-positive colorectal cancer cases. Currently, both molecular targeted agents are available for first-line treatment of RAS wild -type mCRC. However, multiple studies have reported that anti-EGFR antibody therapy is less effective in later-line treatment of HER2-positive mCRC [6, 8, 9]. \u0026nbsp;Indeed baseline circulating tumor DNA analysis [10] in the PARADIGM trial demonstrated higher efficacy of anti-EGFR agents in population without multiple genetic alterations, including \u003cem\u003eHER2\u0026nbsp;\u003c/em\u003eamplification. Consequently, there is no established consensus on the optimal molecular targeted agent for first-line treatment in patients with \u003cem\u003eRAS\u003c/em\u003e wild-type HER2-positive mCRC.\u003c/p\u003e\n\u003cp\u003eSecond, there is a lack of real-world data on the efficacy and safety of Tmab+Per combination therapy, which is currently the most widely used HER2-targeted regimen in clinical practice. The objective response rate (ORR) of this combination in clinical trials is approximately 20\u0026ndash;30% [2, 3], but the data from real-world practice remain limited, making it important to investigate which patients are most likely to benefit. Furthermore, infusion-related reactions (IRRs) have been reported particularly during early treatment cycles [3, 11], but information on the strategies for safe administration in routine clinical practice remains insufficient. Therefore, we conducted a multicenter retrospective observational study to address these clinical questions in patients with HER2-positive mCRC.\u0026nbsp;\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cp\u003e\u003cstrong\u003ePatients, Study Design,\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;and Definition of Human Epidermal Growth Factor Receptor 2-Positivity\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis multicenter retrospective observational study included patients diagnosed with HER2-positive mCRC at 14 institutions in Japan between December 2010 and December 2023. HER2-positive tumors were defined by at least one of the following criteria: i) an immunohistochemistry (IHC) score of 3+, ii) a HER2/CEP17\u0026nbsp;ratio of 2.0\u0026nbsp;or greater by fluorescence in situ hybridization (FISH), and iii)\u0026nbsp;HER2\u0026nbsp;gene amplification detected by next-generation sequencing (NGS) using tissue or liquid biopsy, defined as a copy number of 2.18 or more.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRAS/BRAF Mutation and Microsatellite Instability/Mismatch Repair Status\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRAS\u0026nbsp;and\u0026nbsp;BRAF\u0026nbsp;V600E mutations were analyzed using the RASKET-B kit (Medical \u0026amp; Biological Laboratories, Tokyo, Japan). Microsatellite instability (MSI) status was determined either by a polymerase chain reaction-based MSI panel or by IHC staining for mismatch repair proteins (MutL homolog 1, MutS homolog 2, MutS homolog 6, and Postmeiotic segregation increased 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment Outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn patients with\u0026nbsp;RAS\u0026nbsp;wild-type tumors, the efficacy of first-line doublet or triplet chemotherapy combined with either anti-EGFR antibody or bevacizumab was evaluated. Progression-free survival (PFS) was defined as the time from initiation of first-line therapy to disease progression or death from any cause. Overall survival (OS) was defined as the time from initiation of first-line therapy to death from any cause. ORR was assessed according to the Response Evaluation Criteria in solid tumor version 1.1. The efficacy and safety of Tmab+Per were analyzed in patients who initiated this regimen by July 2024. ORR, disease control rate (DCR), and PFS were assessed according to the Response Evaluation Criteria in solid tumor version 1.1. Adverse events (AEs) were evaluated using the Common Terminology Criteria for Adverse Events version 5.0. The data cutoff date was December 31, 2025.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStatistical Analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analyses were performed using EZR version 1.68 (Saitama Medical Center, Jichi Medical University, Saitama, Japan) and IBM SPSS Statistics version 29.0.1.0 (IBM Japan Ltd., Tokyo, Japan). Categorical variables were evaluated using Fisher\u0026apos;s exact test. Survival curves were estimated using the Kaplan\u0026ndash;Meier method, and hazard ratios (HRs) were calculated using the Cox proportional hazards model. Comparison of PFS between treatment groups was performed using the log-rank test. Statistical significance was defined as a \u003cem\u003ep\u003c/em\u003e-value less than 0.05.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthical Considerations\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted in accordance with the Declaration of Helsinki and approved by the institutional review boards of all participating institutions. Due to the retrospective nature of the study, the requirement for written informed consent was waived.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eB\u003c/strong\u003e\u003cstrong\u003easeline Characteristics of Study Participants\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 45 patients with HER2-positive mCRC were included in this study. Patient clinical characteristics for all 45 patients are shown in Table 1. The median age was 63 years (range, 36\u0026ndash;81 years), and 64.4% were male. HER2 status was determined as follows: 26 patients had HER2 IHC3+, 15 patients were FISH positive (excluding IHC3+), and 4 patients had \u003cem\u003eHER2\u003c/em\u003e gene amplification detected by NGS (excluding IHC3+ and FISH positive).\u003c/p\u003e\n\u003cp\u003ePrimary tumors were located on the left side of the colon or rectum in 73.3% of patients and on the right side in 26.7%. Metastatic sites were most commonly the liver (66.7%), followed by the lung (35.6%). Regarding molecular profiles, 73.3% of patients were \u003cem\u003eRAS\u003c/em\u003e wild-type, and all patients were negative for the \u003cem\u003eBRAF\u003c/em\u003e V600E mutation and MSI-high (MSI-H) status. Detailed results of HER2 testing by IHC, FISH, and NGS, along with corresponding \u003cem\u003eRAS\u003c/em\u003e status for each patient, are summarized in Supplementary Table 1.\u003c/p\u003e\n\u003cp\u003eOf 33 patients with \u003cem\u003eRAS\u003c/em\u003e wild-type tumors, nine received anti-EGFR and seventeen received bevacizumab combined with chemotherapy as first-line treatment (anti-EGFR antibody \u003cem\u003evs\u003c/em\u003e. bevacizumab cohort). Twenty of the 45 patients received Tmab+Per therapy (Tmab+Per cohort). The study flowchart is shown in Figure 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEfficacy of First-Line Therapy in RAS Wild-Type Patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatient characteristics for those with HER2-positive and \u003cem\u003eRAS\u003c/em\u003e wild-type tumors who received first-line chemotherapy with an anti-EGFR antibody (\u003cem\u003en\u003c/em\u003e = 17) or bevacizumab (\u003cem\u003en\u003c/em\u003e = 9) are shown in Supplementary Table 2. PFS and OS according to first-line regimens in patients with HER2 positive/\u003cem\u003eRAS\u003c/em\u003e wild-type are shown in Figures 2A and 2B. At a median follow-up of 43.3 months, first-line PFS was similar between the anti-EGFR antibody (\u003cem\u003en\u003c/em\u003e = 17) and bevacizumab (\u003cem\u003en\u003c/em\u003e = 9) groups (median: 15.6 \u003cem\u003evs\u003c/em\u003e. 12.0 months, HR = 0.94, 95% confidence interval: 0.38\u0026ndash;2.35, \u003cem\u003ep\u003c/em\u003e = 0.89). OS was also similar between the two groups (median: 38.4 \u003cem\u003evs\u003c/em\u003e. 32.0 months; HR = 0.91, 95% confidence interval: 0.30\u0026ndash;2.74, \u003cem\u003ep\u003c/em\u003e = 0.87). The ORR was 58.8% in the anti-EGFR antibody group and 100% in the bevacizumab group, with details provided in Supplementary Table 3.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEfficacy and Safety Profile of\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eTrastuzumab plus Pertuzumab Therapy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of twenty patients received Tmab+Per therapy. Baseline characteristics of these patients are summarized in Table 2. The median age was 65 years (range, 36\u0026ndash;80), with 9 females (45.0%) and 11 males (55.0%). Primary tumors were located more frequently on the left side of the colon or rectum (75.0%) than on the right side (25.0%). Regarding HER2 status, 9 patients (45.0%) had IHC 3+, 7 patients (35.0%) were FISH positive (excluding IHC 3+), and 4 patients (20.0%) had\u0026nbsp;HER2\u0026nbsp;gene amplification confirmed by NGS (excluding IHC 3+ and FISH positive).\u0026nbsp;RAS\u0026nbsp;wild-type status was identified in 15 patients (75.0%), while 5 patients (25.0%) carried\u0026nbsp;RAS\u0026nbsp;mutations. Tmab+Per therapy was administered mainly in later treatment lines; 4 patients (20.0%) as second-line, 1 patient (5.0%) as third-line, 7 patients (35.0%) as fourth-line, 5 patients (25.0%) as fifth-line, and 3 patients (15.0%) as sixth-line therapy. Median relative dose intensity was 97.9% for trastuzumab and 97.7% for pertuzumab, indicating good treatment compliance. Figure 3 shows the PFS for Tmab+Per therapy, along with each patient\u0026rsquo;s HER2-IHC score,\u0026nbsp;RAS\u0026nbsp;status, prior anti-EGFR therapy, and line of therapy. Median PFS for all patients was 3.1 months. The ORR and DCR were 10.0% and 55.0%, respectively. Efficacy by\u0026nbsp;RAS\u0026nbsp;status and HER2 IHC score is shown in Figure 4. Patients most likely to benefit from Tmab+Per treatment were those with\u0026nbsp;RAS\u0026nbsp;wild-type and IHC3+ tumors (median PFS 4.1 months, ORR 28.6%, DCR 71.4%), followed by\u0026nbsp;RAS\u0026nbsp;wild-type without IHC3+ (median PFS 2.2 months, ORR 0%, DCR 37.5%). Among five patients with\u0026nbsp;RAS\u0026nbsp;mutations, only one achieved disease control, with the poorest treatment response (median PFS 2.2 months).\u003c/p\u003e\n\u003cp\u003eAEs related to Tmab+Per therapy were generally manageable (Table 3). The most frequently observed AEs (any grade) included fatigue (40.0%), anorexia (30.0%), anemia (30.0%), and IRRs (30.0%). Grade 3 or more AEs occurred in 15% of patients and included diarrhea (5.0%), IRRs (5.0%), perimandibular inflammation (5.0%), cellulitis (5.0%), and ureteral stones (5.0%). One patient discontinued Tmab+Per therapy due to Grade 4 IRRs.\u003c/p\u003e\n\u003cp\u003eThe frequency of IRRs according to premedication is shown in Table 4. Among 19 patients with available premedication data, IRRs occurred in six patients (three Grade 1, two Grade 2, and one Grade 4). The incidence of IRRs was similar in patients who received acetaminophen or nonsteroidal anti-inflammatory drugs as premedication (n = 9) compared with those who did not (n = 11) (33.0% vs. 30.0%, p = 1.00). IRRs were numerically lower in patients who received antihistamines (n = 7) compared with those who did not (n = 12), although the difference was not statistically significant (14.2% vs. 41.7%, p = 0.35).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this multicenter retrospective study, we investigated the real-world clinical characteristics and treatment outcomes of patients with HER2-positive mCRC. To our knowledge, this study represents the largest multicenter real-world clinical cohort to date. Our data provide unique insights into the clinical characteristics, treatment outcomes, and premedication strategies of IRRs in this rare molecular subtype in routine practice.\u003c/p\u003e\n\u003cp\u003eThe majority of patients in our cohort had left-sided primary tumors with \u003cem\u003eRAS\u003c/em\u003e wild-type status and liver metastases, consistent with previous reports [6, 12]. Prior studies have shown that \u003cem\u003eHER2\u003c/em\u003e amplification is largely mutually exclusive with MSI-H [12], and no patients in this study harbored MSI-H tumors or\u0026nbsp;\u003cem\u003eBRAF\u003c/em\u003e V600E mutations.\u0026nbsp;Furthermore, compared with prior clinical evidence\u0026nbsp;[3], our real-world cohort included a relatively higher proportion of patients defined as HER2-positive by FISH or NGS despite the absence of HER2IHC3+ overexpression. In prospective clinical trials such as DESTINY-CRC01 and TRIUMPH, approximately 75% of patients were classified as having HER2 IHC3+ tumors\u0026nbsp;[3]\u0026nbsp;[4], whereas only 57.8% (26/45) of patients exhibited HER2 IHC3+ overexpression in our study.\u0026nbsp;Because IHC results are not mandatory for the use of anti-HER2 therapy in clinical practice, unlike clinical trials, the presence of a few patients (\u003cem\u003en\u003c/em\u003e = 4, 8.9%) with missing IHC results contributed to this difference. However, the primary reason was the high number of cases showing \u003cem\u003eHER2\u003c/em\u003e gene amplification despite IHC2+ (\u003cem\u003en\u003c/em\u003e = 13, 28.9%). HER2 IHC in our study was performed using the same antibody clone (VENTANA 4B5) as in prospective trials; however, scoring was conducted locally at each participating institution rather than \u003cem\u003evia\u003c/em\u003e centralized review. This difference in assessment methodology may have introduced inter-observer variability and partly explains the discrepancy in HER2 expression profiles between our real-world cohort and clinical trial populations. These findings suggest that when tumors are classified as HER2 IHC2+ by local assessment, confirmatory testing with FISH or NGS may help identify additional tumors with \u003cem\u003eHER2\u003c/em\u003e gene amplification.\u003c/p\u003e\n\u003cp\u003eIn first-line chemotherapy for patients with \u003cem\u003eRAS\u003c/em\u003e wild-type tumors, there were no statistically significant differences in efficacy between the bevacizumab-containing and anti-EGFR antibody groups. Although HER2 overexpression has been proposed as a mechanism of resistance to anti-EGFR therapy based on preclinical and retrospective late-line treatment data [13], a recent pooled exploratory analysis of eight randomized trials demonstrated that HER2 positivity did not predict differential benefit from first-line chemotherapy combined with either anti-EGFR antibodies or bevacizumab\u0026nbsp;[14]. In that analysis, no significant interaction between HER2 status and the choice of biologic agent was observed for PFS, OS, or ORR, indicating that HER2 positivity alone should not guide selection between anti-EGFR- or bevacizumab-based regimens in the first-line setting. Therefore, the lack of significant differences observed in our study aligns with these findings. Clinically, these results support an individualized treatment approach in which the selection of biologic agents is guided primarily by patient-specific factors rather than expected differences in efficacy. In particular, the distinct toxicity profiles of anti-EGFR antibodies (e.g., skin toxicity) and bevacizumab (e.g., hypertension and proteinuria) should be carefully considered when choosing the most appropriate targeted agent for each patient.\u003c/p\u003e\n\u003cp\u003eIn the present study, among patients treated with\u0026nbsp;Tmab+Per, the ORR was 10.0%, DCR was 55.0%, and median PFS was 3.1 months. Compared with previously reported prospective studies, such as the MyPathway and TRIUMPH trials [2] [3], median PFS was generally comparable, whereas the ORR was lower in our cohort. Several differences in patient characteristics may explain this discrepancy. Compared with prior clinical trials, patients treated with Tmab+Per in our study were older, had a higher proportion of \u003cem\u003eRAS\u003c/em\u003e-mutant tumors, and showed a lower frequency of HER2 IHC3+ expression. Among these factors, \u003cem\u003eRAS\u003c/em\u003e mutation status and HER2 IHC score were particularly important. As anti-HER2 therapy is known to be less effective in \u003cem\u003eRAS\u003c/em\u003e-mutant tumors, in the MyPathway study, Tmab+Per demonstrated substantially lower activity in patients with \u003cem\u003eRAS\u003c/em\u003e-mutant tumors (ORR 8%) compared with patients with \u003cem\u003eRAS\u003c/em\u003e wild-type disease (ORR 40%)\u0026nbsp;[2]. The importance of HER2 expression level for anti-HER2 therapy has been demonstrated in the DESTINY-CRC01 trial evaluating trastuzumab deruxtecan, in which patients with HER2 IHC3+ tumors achieved higher ORR (57.5%) and longer median PFS (8.3 months), whereas\u0026nbsp;limited benefit was observed in patients with HER2 IHC2+/FISH positive tumors (ORR 7.7%; median PFS 4.1 months)\u0026nbsp;[4]. Consistently, in our study, treatment efficacy was highest in patients with\u0026nbsp;\u003cem\u003eRAS\u003c/em\u003e wild-type and IHC3+ tumors.\u0026nbsp;Taken together, these findings indicate that careful patient selection based on molecular characteristics, including \u003cem\u003eRAS\u003c/em\u003e mutation status and HER2 expression level, is crucial to maximize the benefit of late-line treatment, including anti-HER2 therapy, in metastatic colorectal cancer.\u003c/p\u003e\n\u003cp\u003eAEs associated with\u0026nbsp;Tmab+Per were generally manageable, suggesting that this combination therapy can be administered with an acceptable safety profile in real-world clinical practice. In the TRIUMPH trial, IRRs, a characteristic AE of Tmab+Per therapy, were reported in 47.0% of patients [3]. IRRs are clinically relevant because their occurrence may lead to treatment interruption or delay, potentially compromising treatment continuity. Therefore, appropriate management and prevention of IRRs are important in clinical practice. In our real-world cohort, IRRs were observed in 31.6% of patients, demonstrating an incidence comparable to that reported in clinical trials. Notably, patients who received antihistamine premedication experienced a numerically lower incidence of IRRs compared with those who did not receive antihistamines (14.2% \u003cem\u003evs\u003c/em\u003e. 41.7%). In clinical practice, premedication with antihistamines or nonsteroidal anti-inflammatory drugs is commonly used to prevent IRRs associated with chimeric monoclonal antibodies such as rituximab [15, 16]. In breast cancer, corticosteroid premedication has also been suggested to reduce the risk of IRRs during trastuzumab therapy in retrospective studies [17]. However, there are currently no prospective or retrospective studies that have specifically evaluated the efficacy of premedication, including corticosteroids or antihistamines, for the prevention of IRRs associated with trastuzumab or pertuzumab therapy in patients with metastatic colorectal cancer. Our findings suggest that antihistamine premedication may reduce the risk of IRRs in this setting.\u003c/p\u003e\n\u003cp\u003eDespite the clinical relevance of these real-world findings, several limitations should be acknowledged. First, this study was limited by its retrospective observational design, which may have resulted in incomplete clinical data and variability in the timing of response assessment and AE reporting. Second, the relatively small sample size, reflecting the rarity of HER2-positive mCRC, may have limited the statistical power to detect differences between treatment groups. Third, there was substantial heterogeneity in patient characteristics and treatment strategies. In particular, the line of therapy at which Tmab+Per was administered varied widely, from third-line to later-line settings, which may have influenced both efficacy and safety outcomes. Fourth, methods used to determine HER2 status were not uniform across institutions and included IHC, FISH, and NGS. This heterogeneity may have introduced variability in the identification of HER2-positive tumors and potentially influenced the study results. Fifth, OS may have been affected by subsequent therapies administered after disease progression. Because post-progression treatment were not standardized in this retrospective study, the impact of individual treatment strategies, including first-line biologic selection and anti-HER2 therapy, on OS should be interpreted with caution.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn clinical practice, first-line treatment regimens should be selected based on patient characteristics, including tumor biomarkers and the distinct toxicity profiles of available therapies. The Tmab+Per combination therapy was effective in real-world clinical settings; however, appropriate patient selection and careful management of IRRs are critical to optimize treatment outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank all participating patients and their families.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eShiho Kaneko and Kentaro Sawada conceived and designed the study. Shiho Kaneko developed the study protocol and obtained ethical approval. Shiho Kaneko collected and curated the data. Kentaro Sawada contributed to data collection and data curation. Kazuteru Hatanaka, Hiroshi Nakatsumi, Masayoshi Dazai, Takayuki Ando, Masahito Kotaka, Yasushi Tsuji, Michio Nakamura, Osamu Muto, Takashi Meguro, Takahiro Ishii, Atsushi Sato, and Susumu Sogabe collected data at their respective institutions. Shiho Kaneko and Kentaro Sawada performed the statistical analysis. Shiho Kaneko and Kentaro Sawada drafted the manuscript. Shintaro Sawaguchi, Tatsuya Yokoyama, Koichi Ishida, Kazuaki Harada, Yasuyuki Kawamoto, Satoshi Yuki, Naoya Sakamoto, Yu Sakata, and Yoshito Komatsu critically revised the manuscript. Yoshito Komatsu supervised the study as the principal investigator and provided overall project oversight. All authors reviewed and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no external funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current multicenter retrospective study are available from the corresponding author on reasonable request, subject to approval by the participating institutions.\u003c/p\u003e\n\u003cp\u003eDeclarations:\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eMasahito Kotaka, Yasushi Tsuji, Satoshi Yuki, and Yoshito Komatsu have received honoraria from Chugai Pharmaceutical Co., Ltd. The remaining authors declare that they have no conflicts of interest.\u003c/p\u003e\n\u003cp\u003eConsent to participate\u003c/p\u003e\n\u003cp\u003eThe requirement for obtaining informed consent from participants was waived owing to the retrospective nature of this study.\u003c/p\u003e\n\u003cp\u003eEthical approval\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the principles outlined in the Declaration of Helsinki and was approved by the Ethics Committee of Hokkaido University Hospital (Clinical Research Number: IRB 023-0470).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBray F, Laversanne M, Sung H et al (2024) Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 74:229\u0026ndash;263. https://doi.org/10.3322/caac.21834\u003c/li\u003e\n\u003cli\u003eMeric-Bernstam F, Hurwitz H, Raghav KPS et al (2019) Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): an updated report from a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol 20:518\u0026ndash;530. https://doi.org/10.1016/s1470-2045(18)30904-5\u003c/li\u003e\n\u003cli\u003eNakamura Y, Okamoto W, Kato T et al (2021) Circulating tumor DNA-guided treatment with pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer: a phase 2 trial. Nat Med 27:1899\u0026ndash;1903. https://doi.org/10.1038/s41591-021-01553-w\u003c/li\u003e\n\u003cli\u003eYoshino T, Di Bartolomeo M, Raghav K et al (2023) Final results of DESTINY-CRC01 investigating trastuzumab deruxtecan in patients with HER2-expressing metastatic colorectal cancer. Nat Commun 14:3332. https://doi.org/10.1038/s41467-023-38032-4\u003c/li\u003e\n\u003cli\u003eRaghav K, Siena S, Takashima A et al (2024) Trastuzumab deruxtecan in patients with HER2-positive advanced colorectal cancer (DESTINY-CRC02): primary results from a multicentre, randomised, phase 2 trial. Lancet Oncol 25:1147\u0026ndash;1162. https://doi.org/10.1016/s1470-2045(24)00380-2\u003c/li\u003e\n\u003cli\u003eSawada K, Nakamura Y, Yamanaka T et al (2018) Prognostic and predictive value of HER2 amplification in patients with metastatic colorectal cancer. Clin Colorectal Cancer 17:198\u0026ndash;205. https://doi.org/10.1016/j.clcc.2018.05.006\u003c/li\u003e\n\u003cli\u003eAhcene Djaballah S, Daniel F, Milani A et al (2022) HER2 in colorectal cancer: the long and winding road from negative predictive factor to positive actionable target. Am Soc Clin Oncol Educ Book 42:1\u0026ndash;14. https://doi.org/10.1200/edbk_351354\u003c/li\u003e\n\u003cli\u003eRaghav K, Loree JM, Morris JS et al (2019) Validation of HER2 amplification as a predictive biomarker for anti-epidermal growth factor receptor antibody therapy in metastatic colorectal cancer. JCO Precis Oncol 3:1\u0026ndash;13. https://doi.org/10.1200/po.18.00226\u003c/li\u003e\n\u003cli\u003eSartore-Bianchi A, Amatu A, Porcu L et al (2019) HER2 positivity predicts unresponsiveness to EGFR-targeted treatment in metastatic colorectal cancer. Oncologist 24:1395\u0026ndash;1402. https://doi.org/10.1634/theoncologist.2018-0785\u003c/li\u003e\n\u003cli\u003eShitara K, Muro K, Watanabe J et al (2024) Baseline ctDNA gene alterations as a biomarker of survival after panitumumab and chemotherapy in metastatic colorectal cancer. Nat Med 30:730\u0026ndash;739. https://doi.org/10.1038/s41591-023-02791-w\u003c/li\u003e\n\u003cli\u003eOtsuji K, Tanabe M, Morizono A et al (2023) Exploring predictive risk factors of infusion reactions with first pertuzumab administration in HER2-positive breast cancer patients: a single institution experience. JMA J 6:63\u0026ndash;72. https://doi.org/10.31662/jmaj.2022-0132\u003c/li\u003e\n\u003cli\u003eLee SM, Oh H (2024) \u003cem\u003eRAS/RAF\u003c/em\u003e mutations and microsatellite instability status in primary colorectal cancers according to HER2 amplification. Sci Rep 14:11432. https://doi.org/10.1038/s41598-024-62096-x\u003c/li\u003e\n\u003cli\u003eBertotti A, Migliardi G, Galimi F et al (2011) A molecularly annotated platform of patient-derived xenografts (\u0026quot;xenopatients\u0026quot;) identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discov 1:508\u0026ndash;523. https://doi.org/10.1158/2159-8290.cd-11-0109\u003c/li\u003e\n\u003cli\u003eGermani MM, Borelli B, Hashimoto T et al (2025) Impact of human epidermal growth factor receptor 2 in patients with metastatic colorectal cancer treated with chemotherapy plus bevacizumab or anti-EGFRs: exploratory analysis of eight randomized trials. J Clin Oncol 43:3184\u0026ndash;3197. https://doi.org/10.1200/jco-25-01003\u003c/li\u003e\n\u003cli\u003eMcLaughlin P, Grillo-L\u0026oacute;pez AJ, Link BK et al (2023) Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 41:154\u0026ndash;162. https://doi.org/10.1200/jco.22.02403\u003c/li\u003e\n\u003cli\u003eBarroso A, Estevinho F, Hespanhol V et al (2024) Management of infusion-related reactions in cancer therapy: strategies and challenges. ESMO Open 9:102922. https://doi.org/10.1016/j.esmoop.2024.102922\u003c/li\u003e\n\u003cli\u003eGoto E, Hata T, Nishihara M et al (2023) Preventive effect of dexamethasone premedication on the development of infusion-related reaction in breast cancer patients receiving trastuzumab. Br J Clin Pharmacol 89:2102\u0026ndash;2112. https://doi.org/10.1111/bcp.15675\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Patient characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"529\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eN=45 (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eAge, year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eMedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e63 (36-81)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e16 (35.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e29 (64.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eECOG PS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e30 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003e\u0026ge;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e15 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003ePrimary tumor location\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eLeft\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e33 (73.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eRight\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e12 (26.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eMetastatic site\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eLiver\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e30 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eLung\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e16 (35.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eLymph nodes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e11 (24.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003ePeritoneal dissemination\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e10 (22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eHER2 positivity diagnosed methods\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eIHC 3+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e26 (57.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eFISH positive (except IHC3+)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e15 (28.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003e\u003cem\u003eHER2\u003c/em\u003e amp on NGS (except IHC 3+ or FISH positive)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e4 (13.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cem\u003eRAS\u003c/em\u003e status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eWild\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e33 (73.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eMutant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e12 (26.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cem\u003eBRAF\u003c/em\u003e V600E status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eWild\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e45 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eMutant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003eMSI status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eNon MSI-H\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e45 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eMSI-H\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviation: ECOG PS, Eastern Cooperative Oncology Group performance status; MSI-H, microsatellite instability-high; IHC, immunohistochemistry; FISH, fluorescence in situ hybridization; NGS, next-generation sequencing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Baseline characteristics of patients who received trastuzumab plus pertuzumab therapy\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"548\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 241px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eN=20 (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003eAge, year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 241px;\"\u003e\n \u003cp\u003eMedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e65 (36-80)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 241px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e9 (45.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 241px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e11 (55.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003ePrimary tumor location\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 241px;\"\u003e\n \u003cp\u003eLeft\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e15 (75.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 155px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 241px;\"\u003e\n \u003cp\u003eRight\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e5 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003eHER2 status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 241px;\"\u003e\n \u003cp\u003eIHC 3+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e9 (45.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 241px;\"\u003e\n \u003cp\u003eIHC 2+ and FISH +\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e7 (35.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 241px;\"\u003e\n \u003cp\u003e\u003cem\u003eHER2\u003c/em\u003e amplification on NGS or FISH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e4 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e\u003cem\u003eRAS\u003c/em\u003e status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 241px;\"\u003e\n \u003cp\u003eWild\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e15 (75.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 241px;\"\u003e\n \u003cp\u003eMutant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e5 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003eTreatment lines\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 241px;\"\u003e\n \u003cp\u003e2nd\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e4 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 241px;\"\u003e\n \u003cp\u003e3rd\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e1 (5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 241px;\"\u003e\n \u003cp\u003e4th\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e7 (35.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 241px;\"\u003e\n \u003cp\u003e5th\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e5 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 241px;\"\u003e\n \u003cp\u003e6th\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e3 (15.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003eRDI of Trastuzumab (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 241px;\"\u003e\n \u003cp\u003eMedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e97.9 (68.6-100)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003eRDI of Pertuzumab (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 241px;\"\u003e\n \u003cp\u003eMedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e97.7 (61.5-100)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003ePrevious treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 241px;\"\u003e\n \u003cp\u003eAnti-EGFR antibody\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e13 (65.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 241px;\"\u003e\n \u003cp\u003eFluoropyrimidine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e19 (95.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 241px;\"\u003e\n \u003cp\u003eOxaliplatin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e19 (95.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 241px;\"\u003e\n \u003cp\u003eIrinotecan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e17 (85.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 241px;\"\u003e\n \u003cp\u003eBevacizumab/Ramucirumab/Aflibercept\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e18 (90.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 241px;\"\u003e\n \u003cp\u003eRegorafenib\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e7 (35.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 241px;\"\u003e\n \u003cp\u003eTrifluridine/tipiracil\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e10 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003ePremedication\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 241px;\"\u003e\n \u003cp\u003eAntihistamine \u0026plusmn; NSAIDs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e5 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 155px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 241px;\"\u003e\n \u003cp\u003eNo antihistamine \u0026plusmn; NSAIDs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e12 (60.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: FISH, fluorescence in situ hybridization; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; NGS, next-generation sequencing; NSAIDs, non-steroidal anti-inflammatory drugs; RDI, relative dose intensity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. AEs related Tmab+Per treatment\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCTCAE v5.0, grade, N=20\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAny grade\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026ge;Grade 3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eWhite blood cell decreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e2 (10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eNeutrophil count decreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e1 (5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eAnemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e6 (30.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e1 (5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003ePlatelet count decreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e3 (15.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e2 (10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eAnorexia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e6 (30.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e8 (40.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e4 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e1 (5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e3 (15.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eInfusion related reactions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e6 (30.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e1 (5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003ePerimandibular inflammation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e1 (5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e1 (5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eCellulitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e1 (5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e1 (5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 208px;\"\u003e\n \u003cp\u003eUreteral stones\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e1 (5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e1 (5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviation: AEs, adverse events; CTCAE, Common Terminology Criteria for Adverse Events; Tmab, trastuzumab; Per, pertuzumab.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4. Frequency of Infusion Related Reactions (IRRs) according to the premedication\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eInfusion Related Reactions\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003eNSAIDs or\u003c/p\u003e\n \u003cp\u003eAcetaminophen (+)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003eNSAIDs or\u003c/p\u003e\n \u003cp\u003eAcetaminophen (-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003eAntihistamine (+)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e1/6 (16.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e0/1 (0.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e1/7 (14.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003eAntihistamine (-)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e2/3 (66.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e3/9 (33.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e5/12 (41.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e3/9 (33.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e3/10 (30.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e6/19 (31.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviation: NSAIDs, nonsteroidal anti-inflammatory drugs.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"human epidermal growth factor receptor 2-positive metastatic colorectal cancer, trastuzumab plus pertuzumab, RAS wild-type, first-line chemotherapy, infusion-related reactions","lastPublishedDoi":"10.21203/rs.3.rs-9232486/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9232486/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn metastatic colorectal cancer (mCRC), human epidermal growth factor receptor 2 (HER2)-positive disease is an important molecular subtype for targeted therapy; however, its prevalence is low and real-world data remain limited.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA multicenter retrospective study of patients with HER2-positive mCRC diagnosed between 2010 and 2023 at 14 institutions in Japan was conducted. In patients with \u003cem\u003eRAS\u003c/em\u003e wild-type tumors, clinical outcomes were compared based on the molecular targeted agent (anti- epidermal growth factor receptor [EGFR] antibody or bevacizumab) combined with first-line chemotherapy. In patients treated with trastuzumab plus pertuzumab, clinical outcomes and safety including infusion-related reactions (IRRs) were assessed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eForty-five patients were included. In patients with \u003cem\u003eRAS\u003c/em\u003e wild-type tumors, clinical outcomes were comparable between the anti-EGFR antibody (\u003cem\u003en\u003c/em\u003e = 17) and bevacizumab (\u003cem\u003en\u003c/em\u003e = 9) groups (progression-free survival: 15.6 \u003cem\u003evs\u003c/em\u003e. 12.0 months; hazard ratio: 0.94, 95% confidence interval: 0.38–2.35, overall survival: 38.4 \u003cem\u003evs\u003c/em\u003e. 32.0 months; hazard ratio: 0.91, 95% confidence interval: 0.30–2.74, \u003cem\u003ep\u003c/em\u003e = 0.87). Twenty patients received trastuzumab plus pertuzumab, with a median progression-free survival of 3.1 months and an objective response rate of 10%. Greater benefit was observed in patients with \u003cem\u003eRAS\u003c/em\u003e wild-type and HER2 immunohistochemistry\u003cbr\u003e\n \u0026nbsp;3+ tumors (objective response rate 28.6%). IRRs occurred in 14.2% of patients who received prophylactic antihistamines and 41.7% of those who did not.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn patients with HER2-positive mCRC, first-line treatment efficacy appeared comparable between the anti-EGFR antibody and bevacizumab groups. Trastuzumab plus pertuzumab demonstrated clinical activity, emphasizing the importance of appropriate patient selection and management of IRRs.\u003c/p\u003e","manuscriptTitle":"A Multicenter Retrospective Study on the Clinical Features of Patients with Human Epidermal Growth Factor Receptor 2-Positive Colorectal Cancer (HGCSG2304)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-29 06:15:01","doi":"10.21203/rs.3.rs-9232486/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revisions","date":"2026-05-08T00:53:08+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2026-04-20T21:18:13+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-20T13:03:41+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-26T14:00:15+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Clinical Oncology","date":"2026-03-26T05:53:01+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"75c5d2c1-436f-48c6-ba40-a9fa7bac0d16","owner":[],"postedDate":"April 29th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Major revisions","date":"2026-05-08T00:53:08+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-05-08T04:55:01+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-29 06:15:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9232486","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9232486","identity":"rs-9232486","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}